The present invention relates to a method of preparing pure 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one and a pharmaceutically acceptable salt thereof in a high yield.
1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one of formula (I), which is used as an anti-vomiting agent due to its selective action on 5-HT3 receptors, is prepared by various methods. 
For example, Korean Patent Publication No. 92-1670 discloses a method of preparing the compound of formula (I) described in Scheme 1 and Korean Patent Publication No. 92-1671, a method illustrated in Scheme 2. However, these methods have the problem that the overall yield of the final product is very low, e.g., in the range of 4-9%. 
Although improved methods for preparing the subject compound are disclosed in Korean Patent Publication No. 92-3064 (Scheme 3) and in Korean Patent Publication Nos. 98-32228 and 98-32229 (Scheme 4), respectively, their overall yield of the compound of formula (I) is still low, i.e., about 60% or less. 
wherein R2 and R3 are each independently an alkyl group.
Accordingly, it is a primary object of the present invention to provide a simple, high-yield process for preparing 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one and a pharmaceutically acceptable salt thereof.
In accordance with one aspect of the present invention, there is provided a method of preparing the subject compound of formula (I), or a pharmaceutically acceptable salt thereof, which comprises reacting 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (II) with a 2-methylimidazole derivative of formula (III) in an organic solvent or in a mixture of an organic solvent and water, in the presence of a halosilane compound: 
wherein R1 is N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino, morpholin-4-yl, piperidin-1-yl or pirrolidin-1-yl.
1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (II) may be prepared in accordance with the method disclosed in [J. Org. Chem., 1980, 45, 2938] and [J. Org. Chem., 1979, 44, 1236], and it is commercially available. Also, a 2-methylimidazole derivative of formula (III) may be prepared in accordance with the method disclosed in [Tetrahedron Lett., 1990, 31(40), 5779] and [J. Org. Chem., 1988, 53, 5685], representative examples thereof including 1-(N,N-dimethylaminomethyl)-2-methylimidazole, 1-(NN-diethylaminomethyl)-2-methylimidazole and 1-(N-morpholinyl)-2-methylimidazole.
In accordance with the present invention, the compound of formula (III) is employed in an amount ranging from 1 to 5 equivalents, preferably from 1 to 2 equivalents, based on the amount of the compound of formula (II).
Exemplary halosilane compounds which may be used in the inventive reaction include chlorotrimethylsilane, iodotrimethylsilane and t-butyldimethylchlorosilane, and the halosilane compound is used in an amount ranging from 0.5 to 5 equivalents, preferably from 1 to 3 equivalents, based on the amount of the compound of formula (II).
The inventive reaction may be performed at a temperature ranging from a room temperature to 150xc2x0 C., preferably from 80 to 120xc2x0 C., for a period ranging from 2 to 12 hours, preferably from 6 to 8 hours, in an organic solvent such as methylene chloride, chloroform, acetonitrile, tetrahydrofurane, 1,4-dioxane, toluene, N,N-dimethylformamide, ethanol and a mixture thereof, or in a mixture of one of the above organic solvents and water to induce precipitation of the product.
The reaction mixture is then cooled to room temperature. The crystals thus formed are filtered and washed with water, acetone, acetonitrile or isopropylalcohol, and dried, and the resulting product is recrystallized or purified by a conventional method to give a highly pure form of the compound of formula (I) in a high yield.
In addition, the above reaction mixture may be worked up to provide a pharmaceutically acceptable salt of the compound of formula (I). For example, a solvent such as acetone, acetonitrile and isopropylalcohol is added to the reaction mixture, and the resulting mixture is treated with hydrochloric acid to give hydrochloride dihydrate of the compound of formula (I); or an aqueous hydrochloric acid solution is added to the reaction mixture, and the resulting mixture is crystallized and purified by a conventional method to give hydrochloride of the compound of formula (I).
Optionally, 2-methylimidazole may be added to the reaction mixture to further improve the purity and yield of the desired compound. Said 2-methylimidazole is used in an amount ranging from 1 to 5 equivalents, preferably from 1 to 2 equivalents, based on the amount of the compound of formula (I).
The method of the present invention is very simple and provides a highly pure compound of formula (I) and a pharmaceutically acceptable salt thereof in a high yield.